Prostate and pancreatic cancers are among the most common and difficult to treat cancers. Major dilemmas in the management of prostate cancer include the difficulty of discriminating between aggressive and indolent forms of the disease and the need for improved treatment of high-risk and castrate resistant metastatic disease. In the case of pancreatic cancer, the major problems are late diagnosis and high lethality. One major barrier to progress and an unmet need in both diseases is the relative absence of effective molecular imaging tracers/tools that can guide patient management. Antibodies can provide highly specific probes for molecular targets, and can be combined with positron emission tomography (PET) to provide sensitive and quantitative detection. Novel immunoPET imaging agents will be developed based on engineered antibody fragments directed towards Prostate Stem Cell Antigen (PSCA), a cell surface biomarker expressed by a majority of prostate and pancreatic cancers which is also a promising therapeutic target. Two fragment formats, cys- diabody and cys-minibody, will be evaluated to explore their different kinetics and clearance routes in vivo and identify the optimal format(s) for imaging prostate and pancreatic cancer. Protein engineering will be employed to generate multifunctional fragments that can be radiolabeled with positron-emitting radionuclides 124I, 89Zr, or 18F using a variety of conjugation strategies. Promising PSCA-targeted antibody agents will be evaluated by immunoPET in mouse models of prostate cancer disease progression and in genetically engineered mouse models of prostate cancer. Candidate engineered fragments will also be used to image pancreatic ductal adenocarcinoma in xenograft and genetically engineered mouse models of pancreatic cancer. These fully humanized immunoPET probes can be readily translated to the clinic to address pressing questions in clinical management, including staging of newly diagnosed, recurrent and metastatic prostate and pancreatic cancers; quantification of PSCA expression in vivo to improve selection and classification of patients for PSCA-targeted therapy; and monitoring disease response to therapy, particularly in sites such as bone where cancer-specific imaging is difficult (e.g. prostate cancer).